Rosacea, alternatively known as acne rosacea, is a chronic inflammatory eruption of the nose and adjoining flush areas of the face. Rosacea is characterized by erythema, papules, pustules, telangiectasia and, frequently, by hypertrophy of the sebaceous glands.
This disorder of the skin occurs most often in middle-aged women between the ages of thirty and fifty, however, serious cases have been observed in men. Rosacea, in mild form, brings about a slight flushing of the nose and cheeks and, in some cases, the forehead and chin. However, in a severe form, lesions appear which are deep or purplish red and which include a chronic dilation of the superficial capillaries, this constituting the above-referenced telangiectasia. Also, in severe form, inflammatory acneiform pustules are present. In such serious conditions, the eye or eyelids may become affected. Another acute form of rosacea is known as granulomatous rosacea and, as such, is considered to be a distinctive form of the papular aspect of the disease. Therein, discreet pustules appear as yellowish brown nodules and as epithelioid cell granulomatous.
The etiology of rosacea is not fully known, however, at least four factors or co-factors have been suggested.
The first of these is endocrine in that the disease occurs most frequently in women between the ages of thirty and fifty. As such, one definite type of rosacea is believed to have a hormonal basis.
A second factor is vasomotor lability, believed to have some connection with menopause, which brings about an impairment of normal or consistent flow of blood to the face and its capillaries. Therein, excessive flow of blood to the face, i.e., the well-known "hot flashes" of menopause, are believed to constitute a factor in the disease and its pathogenesis. More particularly, it has been proven that increased skin temperature, as occurs in facial flushing, increases susceptibility to the condition.
Rosacea has also been observed as a side effect or immune response to the use of certain cortisone products, which can bring about a severe form of the condition.
Finally, pathology analysis of the expressed contents of inflamed pustule follicle of the nose in acute rosacea has demonstrated the existence of demodices, which is a signature of the ectoparasite demodex folliculorum. Accordingly, in such cases, a specific external pathogenic factor is evident. This factor is not present in other forms of acne, e.g., acne vulgaris.
After contraction of rosacea, its histology will vary in accordance with the stages of the disorder. Typically, there is a disorganization of the upper dermal connective tissue with edema, disruption of fibers, and often severe elastosis. The inflammatory phase of the disease is marked by the presence of inter- and intra-cellular disorganization.
In the prior art, the treatment of choice has been long-term oral administration of tetracycline on a minimum maintenance dose basis. However, studies have shown that this treatment is only suppressive, not curative. Further, metronidazole has been shown to be as effective as tetracycline, however, it is not as safe when given on a long-term basis. Metronidazole cream, marketed under the mark METROGEL, appears to be safer than the oral forms of metronidazole.
Other agents, for example, isotretinoin, sold under the mark ACCUTANE, produce immediate improvement, however, relapse within a few weeks is typical. The topical antibiotic erythromycin is now used on a long-term daily basis in the management of rosacea. However, as may be appreciated from the above, rosacea has proven to be a recalcitrant condition. Where the menopausal factor is involved, treatment with estrogens has been found to be of value.
Another topical therapy, which is useful in patients that can tolerate it, is benzoyl peroxide gel. However, irritation and burning are common side effects of the use of benzoyl peroxide.
From the above, it may be appreciated that the study and treatment of rosacea has been a long-time concern of the medical community. For example, about 1,000 medical papers have been published on the subject. In addition, approximately 30 U.S. patents exist which are directed to methods or medicinals for use in the treatment of acne rosacea. Such patents which are directed to topical preparations for such treatment are U.S. Pat. No. 4,133,983 (1979) to Spangle, entitled Topical Treatment of Skin Diseases; U.S. Pat. No. 5,569,651 (1996) to Garrison, entitled Gentle Anti-Acne Composition; U.S. Pat. No. 5,654,013 (1997) to Taylor, entitled Method for Treating Rosacea; and U.S. Pat. No. 5,744,156 (1998) to Lacharriere, entitled Use of Substance P Antagonist for the Treatment of Skin Reddening of Neurogenic Origin.
Among the above referenced 1000 medical papers and 30 United States patents, no reference teaches or suggests the utility of the composition invermectin in the treatment of acne rosacea or of any other form of acne. Invermectin itself has, historically, been a product of Merck & Co., Inc., Rahway, N.J. and, for the most part, has been used in veterinary applications for the treatment of endoparasitic conditions in animals. However, some medical papers suggest a topical use of invermectin in humans in the treatment of dermatologic manifestations of endoparasitic conditions such as myiasis and onchocerciasis. These conditions bear no etiologic or histologic connection to acne rosacea or any other form of acne. Demodex, referred above, is caused by a near microscopic ectoparasite, not a macroscopic endoparasite.
Invermectin is a part of a larger chemical family known as the nitro-5-imidazoles which, alternatively, has been termed the 13-deoxy invermectin aglycones. The nitro-5-imidazole family of molecules includes invermectin, ivermectin, avermectin, moxidecion and various derivatives thereof.
The present invention thereby relates to a method of treatment of rosacea and a new use of invermectin in such treatment.